This invention relates to the treatment of essential hypertension by administration of anti-hypertensive effective amounts of nitroxides, such as 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol or TMPN).
Systemic hypertension is the most prevalent cardiovascular disorder in the United States, affecting more than 50 million individuals. Accordingly, efforts to prevent, diagnose and treat hypertension remain an important concern of national health care. Although major advances have been made as to public awareness of the importance of hypertension, introducing antihypertensive therapies and in controlling hypertension, the adverse metabolic effects of some classes of antihypertensive drugs and the disappointing results in preventing associated coronary disease have challenged the traditional approaches of treating the antihypertensive patient.
Essential Hypertension
Essential hypertension represents a collection of genetically based diseases and/or syndromes with a number of underlying inherited biochemical abnormalities which have yet to be elucidated. Hypertension leads to atherosclerosis and other forms of vascular pathology by damaging the endothelium. Endothelial damage produces a cascade of changes. Additionally, non-atherosclerotic hypertension-induced vascular damage can lead to stroke and end-stage renal disease. The measurement of blood pressure (BP) is one of the major methods of diagnosing essential hypertension. However, blood pressure is just one factor that is taken into account in the choice of therapy and drug selection for the treatment of the complex pathology which is essential hypertension.
Reactive Oxygen Species
Reactive oxygen species (ROS), such as superoxide anions (O2xe2x88x92), hydroxyl radicals, and hydrogen peroxide (H2O2) have been implicated in atherosclerosis, diabetes, ischemia-reperfusion injury and hypertension (Giugliano et al., 1995 Metab. 44: 363-368; Harrison et al., 1995 Am. J. Cardiol. 75: 75B-81B; McCord et al., 1985 312: 159-163; and Kitiyakara et dl., Curr. Opin. Nephrol Hypertens. In press). Compared to normotensive individuals, hypertensive patients have higher plasma hydrogen peroxide, superoxide anion and lipid peroxides while having lower levels of the antioxidant, ascorbic acid (Lacy et al., 1998 J. Hypertens. 16: 291-303; Kumar et al., 1993 Free Rad. Res. Commun. 19: 59-66; Tse et al., 1994 J. Hum. Hypertens. 89: 843-849; Bulpitt et al., J. Hypertens. 8: 1071-1075). However, the molecular mechanism for oxygen toxicity in vascular diseases, such as essential hypertension, remains to be elucidated.
Enzymes such as superoxide disumutase (SOD) catalyze the dismutation of superoxide radicals to remove the radicals from the subject""s system where the radicals can destroy tissue. Experiments in which SOD was administered to rats did not reduce blood pressure in either normal rats or in spontaneously hypersensitive rats (SHR). However, an SOD fusion protein and oxypurinol, an inhibitor of xanthine oxidase, when administered separately have decreased blood pressure in SHR, but not normal rats (Nakazono et al., 1991 Proc. Nat""l Acad. Sci. USA 88: 10045-10048). Other short term studies of ROS inhibition have indicated that blood pressure can be reduced in the SHR animal model (Yoshioka et al., 1985 Int. J. Vitam. Nutri. Res. 55: 301-307; Nakazono et al., 1991 Proc. Natl Acad. Sci. USA 88: 10045-10048; Suzuki et al., 1998 Proc. Natl Acad. Sci. USA 95: 47544759; Susuki et al., 1995 Hypertens. 25: 1083-1089). Another antioxidant, ascorbic acid, has also lowered the blood pressure level in the SHR animal model. However, the SHR model has also indicated abnormalities in ascorbic acid metabolism (Yoshioka et al., 1985 Internat. J. Vit. Nutr. Res. 55: 301-307). This evidence indicates that superoxide radicals in and around vascular endothelial cells play roles in the pathogenesis of hypertension in the SHR model.
Nitric oxide (NO), also known as endothelium-derived relaxing factor (EDRF), is synthesized by nitric oxide synthase (NOS) in many types of cells including vascular endothelial cells, vascular smooth muscle cells, activated macrophages, neuronal cells and glial cells (Miyamoto et al., 1996 Proc. Soc. Exp. Biol. Med. 211: 366-373). Gryglewski et al., (1986 Nature 320: 454-456) showed that O2xe2x88x92 reacts with NO to form the potentially toxic molecular species, peroxynitrite (ONOOxe2x88x92), which can effectively deplete NO in vascular endothelial cells. Rubanyi et al., (1986) demonstrated that O2xe2x88x92 inactivates EDRF in coronary artery rings (Am. J. Physiol. 250: H822-H827.) Scavenging of O2xe2x88x92 enhances endothelium-dependent vasodilation and increases NO release from mesenteri arterioles (Tschudi et al., 1996 Hypertens. 27: 32-35) and endothelial cells (Grunfeld et al., 1995 Hypertens. 26: 854-857) in SHR. However, the complete mechanism for the vasodilatory actions of O2xe2x88x92 scavengers has yet to be elucidated. Specifically, although in vitro evidence exists suggesting that O2xe2x88x92 contributes to increased systemic vascular tone in the SHR, the role of O2xe2x88x92 in increased renal vascular resistance (RVR) and baseline mean arterial pressure (MAP) of SHR in vivo remains unclear (Schnackenberg et al., 1998 Hypertens. 32: 59-64).
There are many other examples in which severe oxidative stress is found without hypertension. These include, for examples, poisoning with carbon tetrachloride, diabetes mellitus and hypercholesteremia. Indeed, the evidence for oxidative stress in these conditions is better than in hypertension. Therefore, the finding that correction of oxidative stress also reduced blood pressure is not predictable (Kitiyakara et al., in press).
Nitroxides
Nitroxides have been used in ameliorating the deleterious effects of toxic oxygen-related species such as O2xe2x88x92 (see Mitchell et al., 1995 U.S. Pat. No. 5,462,946; Hsia 1997 and 1998 U.S. Pat. Nos., 5,591,710; 5,725,839; 5,741,893; 5,767,089; 5,804,561; and 5,807,831; and Lee et al., 1996 U.S. Pat. No. 5,516,881). Some nitroxides, such as Tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy), have been indicated for use in treating renal hypertension disorders (Carney et al., 1997 U.S. Pat. No. 5,622,994; WO 92/22290). However, renal hypertension occurs as a result of reduced blood flow to the kidney and is not essential hypertension.
The treatment of essential hypertension has long presented a serious problem to the medical profession. This invention proposes a new method of treating essential hypertension in a subject, such as a human, using compositions containing nitroxides. The nitroxides contemplated for use in the treatment of essential hypertension include nitroxides selected from the group consisting of TEMPO, DOXYL or PROXYL nitroxides. One preferred nitroxide is 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol).
This invention also contemplates a method of treating a patient with essential hypertension comprising the step of administering a blood pressure lowering amount of a nitroxide, preferably in admixture with a pharmaceutically acceptable carrier and/or an excipient. This method utilizes the same nitroxides and methods of administration as described above.
Methods of administering pharmaceutical compositions containing nitroxides for treatment of essential hypertension include oral, transdermal, parenteral and intravenous routes of administration.
This invention also provides for a method of treating essential hypertension comprising the steps of administering to a subject, such as a human, any of the above pharmaceutical compositions in combination with a second anti-hypertensive agent (e.g., benzothiadiazine diuretics, loop diuretics, potassium-sparing diuretics, sympatholytic agents, angiotensin-converting enzyme inhibitors, calcium channel blocking agents, direct vasodilators, as well as other antioxidants).
The invention likewise provides ranges of disclosed agents such as Tempol to be administered to a subject for the treatment of essential hypertension. The pharmaceutical compositions of Tempol to be administered to a subject include an intravenous dose of from about 0.07 mg/kg/hr to about 750 mg/kg/hr; an intravenous bolus dose of from about 0.025 mg/kg/day to about 400 mg/kg/day; and an oral dose from about 0.05 mg/kg/day to about 1,000 mg/kg/day.
This invention also contemplates simultaneously treating essential hypertensive and oxidative stress comprising the step of administering a pharmaceutical composition comprising an effective amount of a nitroxide, such as Tempol. Such composition could further comprise additional antihypertensives and/or No providing agents.